Geiser Marianne, Stoeger Tobias, Casaulta Marco, Chen Shanze, Semmler-Behnke Manuela, Bolle Ines, Takenaka Shinji, Kreyling Wolfgang G, Schulz Holger
Institute of Anatomy, Medical Faculty, University of Bern, CH-3012 Bern, Switzerland.
Part Fibre Toxicol. 2014 Apr 24;11:19. doi: 10.1186/1743-8977-11-19.
Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations.
Chloride channel defective CftrTgH (neoim) Hgu mice were used to analyze lung function, lung distribution and whole body biokinetics of inhaled NP, and inflammatory responses after intratracheal administration of NP. Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation. NP biokinetics was deduced from total and regional lung deposition and from whole body translocation of inhaled 30-nm iridium NP within 24 h after aerosol inhalation. Inflammatory responses were assessed within 7 days after carbon NP instillation.
Cftr mutant females had moderately reduced lung compliance and slightly increased airway resistance compared to wild type mice. We found no genotype dependent differences in total, regional and head deposition or in secondary-organ translocation of inhaled iridium NP. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. The twofold increase of bronchoalveolar lavage (BAL) neutrophils in Cftr mutant compared to wild type mice at day 3 but not at days 1 and 7, indicated an impaired capacity in inflammation resolution in Cftr mutants. Concomitant to the delayed decline of neutrophils, BAL granulocyte-colony stimulating factor was augmented in Cftr mutant mice. Anti-inflammatory 15-hydroxyeicosatetraenoic acid was generally significantly lower in BAL of Cftr mutant than in wild type mice.
Despite lacking alterations in lung deposition and biokinetics of inhaled NP, and absence of significant differences in lung function, higher uptake of NP by alveolar epithelial cells and prolonged, acute inflammatory responses to NP exposure indicate a moderately increased susceptibility of lungs to adverse effects of inhaled NP in Cftr mutant mice and provides potential mechanisms for the increased susceptibility of CF patients to air pollution.
囊性纤维化（CF）患者面临环境空气污染对健康产生影响的风险，但对于纳米颗粒（NP）与CF肺部的相互作用了解甚少。在此，我们研究吸入性NP在小鼠CF模型中的分布，旨在揭示导致吸入颗粒对易感人群产生不良影响的机制。
使用氯离子通道缺陷型CftrTgH（neoim）Hgu小鼠分析吸入性NP的肺功能、肺分布和全身生物动力学，以及气管内给予NP后的炎症反应。在吸入NP 1小时后立即和24小时后，在超薄切片上评估20纳米二氧化钛NP在肺中的分布。NP生物动力学由总肺沉积和区域肺沉积以及吸入30纳米铱NP在气溶胶吸入后24小时内的全身转运推导得出。在碳NP滴注后7天内评估炎症反应。
与野生型小鼠相比，Cftr突变雌性小鼠的肺顺应性略有降低，气道阻力略有增加。我们发现吸入铱NP在总沉积、区域沉积和头部沉积或次级器官转运方面没有基因型依赖性差异。吸入二氧化钛导致Cftr突变体中肺泡上皮细胞对NP的摄取更高。滴注碳NP在两种基因型中均诱导了相当的急性和短暂炎症反应。在第3天，Cftr突变体小鼠支气管肺泡灌洗（BAL）中性粒细胞比野生型小鼠增加了两倍，但在第1天和第7天没有增加，这表明Cftr突变体小鼠炎症消退能力受损。与中性粒细胞延迟下降同时，Cftr突变体小鼠BAL中的粒细胞集落刺激因子增加。抗炎性15-羟基二十碳四烯酸在Cftr突变体的BAL中通常显著低于野生型小鼠。
尽管吸入性NP的肺沉积和生物动力学没有改变，且肺功能无显著差异，但肺泡上皮细胞对NP的摄取增加以及对NP暴露的急性炎症反应延长，表明Cftr突变体小鼠肺部对吸入性NP不良影响的易感性略有增加，并为CF患者对空气污染易感性增加提供了潜在机制。
